Von Economo Neurons (VENs) are spindle-shaped bipolar projection neurons that are uniquely situated in the anterior cingulate cortex (ACC) and the fronto-insular cortex (FI) of the human brain. VENs are speculated to be involved in complex social-emotional functions and studies have shown a significant reduction of VENs in the ACC and FI in brain specimens from individuals diagnosed with behavioral variant frontotemporal dementia (bvFTD), a dementia syndrome characterized by changes in personality and socially inappropriate behavior. In particular, ACC VEN loss has been shown to be selectively vulnerable to the TDP-43 pathologic subtype of frontotemporal lobar degeneration (FTLD-TDP) which gives rise to the bvFTD phenotype (Nana et al., 2020). This study investigated the density of VENs in two distinct tauopathy subtypes of FTLD: the 4R tauopathies of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) and the 3R tauopathy of Pick’s disease (PiD).

Density of VENs and total neurons  were quantitated using unbiased stereological methods in the ACC of postmortem samples from 12 right-handed participants from the Northwestern Alzheimer’s Disease Research Center, all of whom carried a clinical diagnosis of bvFTD and FTLD-tau as the primary pathological diagnosis (PiD, N = 4; CBD, N = 4; PSP, N = 4). Five sections of the ACC were stained for Nissl substance to visualize neurons including VENs. Modified stereological methods (Microbrightfield StereoInvestigator) were used to determine the density of neurons. Statistical analyses included ANOVAs and non-parametric t-tests to compare 1) Mean VEN density; 2) Mean neuronal density; and 3) the ratio of VEN/total neuronal density across groups.

There were no significant differences in age between the 3R vs 4R FTLD-tau groups. Analyses demonstrated a decrease in VENs relative to total neuronal density in 3R (PiD) versus 4R (CBD and PSP) which trended toward significance (p=0.15). Though VEN densities were lowest in the PiD group compared to CBD and PSP, results did not reach statistical significance. Additionally, total density of neurons was significantly higher in the group with PiD pathology when compared with the groups with CBD or PSP pathology (p<0.05).

Preliminary results suggest that VENs in the human ACC may be differentially vulnerable to the 3R FTLD-tau species of PiD compared to 4R FTLD-tau species (PSP and CBD).  Additional cases are necessary to confirm clinicopathologic concordance between the bvFTD phenotype and selective loss of VENs to specific FTLD-tau species. Findings will ultimately help clarify the role of this unique cell population in normal human behavior and its susceptibility to neurodegenerative disease.